1. Technical Field
This invention relates generally to a method for producing crystals of a desired size and form and a process for screening the crystals and the crystallization conditions. More particularly, this invention relates to a method in which a large number of crystals of a desired size and form can be produced quickly and reproducibly for use in the testing and screening of crystallization conditions, such as the production of crystals in metastable states and the screening of the crystals for different polymorphic forms.
2. Prior Art
Specific conditions are necessary to crystallize chemical materials with a specific polymorph crystal form and size. Such conditions include the pH, temperature, ionic strength, and specific concentrations of salts, organic additives, detergents, and impurities in the solution. As different condition may allow the generation of different forms and sizes of the crystals, it is often difficult to achieve or obtain the specific condition for crystallizing a crystal with a specific form and size. As such, it is often useful to screen and test conditions that may potentially be suitable for crystal growth.
Crystallization from solution is an important separation and purification process in the chemical process industries. It is a primary method for the production of a wide variety of materials ranging from inorganic compounds to high value-added materials. In addition to product purity, crystallization must also produce particles of the desired size and shape, as well as particles of the desired polymorph.
Chemical species have the ability to crystallize into more than one distinct structure. This ability is called polymorphism (or, if the species is an element, allotropism). Different polymorphs of the same material can display significant changes in their properties, as well as in their structures. These properties include density, shape, vapor pressure, solubility, dissolution rate, bioavailability, and electrical conductivity. Polymorphism is quite common among the elements and also in inorganic and organic species. It is especially prevalent in organic molecular crystals, which often possess multiple polymorphs. The incidence of polymorphism in organic molecular crystals bears great significance to the pharmaceutical, dye, agricultural, chemical, and explosives industries.
Under a given set of conditions, one polymorph exists as the thermodynamically stable form. This is not to say, however, that the other polymorphs cannot exist or form in these conditions. It means only that one polymorph is stable while the other polymorphs can transform to the stable form. For example, acetaminophen can exist in two forms. The thermodynamically stable phase has a monoclinic form of space group P21/n. A second, less stable phase can be obtained; this phase is orthorhombic (space group Pbca) and has a higher density indicative of a closer packing of the molecules.
Often, particularly in solution systems, the polymorph in the metastable state (a β-polymorph, for example) will convert to the polymorph in the stable state (an α-polymorph, for example). However, the β-polymorph may have the more interesting, or at least other interesting, properties. In pharmaceutical product development, the most stable polymorph has, generally, been selected for employment in the final dosage product. Yet metastable forms have often been utilized due to their enhanced dissolution and/or bioavailability. In these cases, an understanding of the stability of these metastable forms under processing and storage conditions has proven crucial for the safety and efficacy of the drug. The United States Food and Drug Administration regulates both the drug substance and the polymorph for all crystalline pharmaceuticals and requires extensive studies of polymorph stability.
To develop the optimal delivery method for a particular drug in the pharmaceutical industry, there exist two very important factors. These include the control of particle (crystal) size and shape and the production of the correct polymorph. In recent years, an increased interest in new drug delivery systems has developed, turning attention to direct injection (intravenous) methods and inhalation. These methods necessitate precise control of particle size, shape, and polymorph produced. Direct inhalation requires particles in the 1-3 micron range while direct injection requires particles in the 100-500 nanometer range.
Many different techniques are employed for particle size reduction, such as supercritical fluid crystallization, impinging jet crystallization, milling, and spray drying. However, each technique has its drawback. For instance, milling requires heat and, as a result, the solid may thermally degrade. Spray drying, supercritical fluid based crystallization, and other crystallization-based methods are contingent on the creation of a very high supersaturation, thus favoring particle nucleation over growth. While effective in making small particles, high supersaturation often results in amorphous materials or an undesired polymorph, rather than the desired form of the crystalline compound. This is particularly true in the case of organic molecular crystals, in which the forces holding the molecules together in the lattice prove relatively weak.
Crystallization from solution generally begins with the nucleation of crystals followed by the growth of these nuclei to finite size. Nucleation and growth follow separate kinetic regimes with nucleation normally being favored at high driving forces (supersaturation) and growth being favored at low supersaturations. Since the ratio of the rate of nucleation to growth during a crystallization process determines the crystal size distribution obtained, this means that high supersaturations are normally employed to produce small crystals. In attempting to produce crystals in the 105 micron range and crystals below 1 micron, this has led to the use of methods that produce very large supersaturations such as supercritical fluid crystallization and crystallization from an impinging jet. Both of these methods suffer from significant problems. One problem is that substances that form organic molecular crystals can be difficult to nucleate under high supersaturations and often produce amorphous material instead of the desired crystals. Another problem is that these methods are difficult to control, design and scale-up and have had little commercial success. A third problem is that these methods can produce an undesired polymorph because of the high levels of supersaturation used.
Organic monolayer films have been used as an interface across which geometric matching and interactions, such as van der Waals forces and hydrogen bonding, can transfer order and symmetry from the monolayer surface to a growing crystal. Nucleation and growth of organic crystals, nucleation rates, polymorphic selectivity, patterning of crystal, crystal morphology, and orientation (with respect to the surface) can undergo modification through site-directed nucleation. This can be achieved using supramolecular assemblies of organic molecules, such as chemically and spatially specific surfaces. Compressed at the plane of water/air interface, Langmuir monolayers are mobilized by, and commensurate with, the adsorption of aggregates during crystallization.
Self-assembled monolayers (SAMs) are single layers of ordered molecules adsorbed on a substrate due to bonding between the surface and molecular head group. SAMs are molecular units that are spontaneously formed upon certain substrates, such as gold and silicon, when immersed in an organic solvent. One of the better known methods to form SAMs is when alkanethiol molecules chemisorb on gold surfaces through the thiol head group to reproducibly form densely packed, robust, often crystalline monolayer films. The surface chemical and physical properties of the monolayer films can be controlled precisely by varying the terminal chemical functionality of the alkanethiol molecule.
SAMs and mixed SAMs lack the mobility of molecules at an air-water interface and, hence, lack the ability to adjust lateral positions to match a face of a nucleating crystal. This is especially true for SAMs of rigid thiols, for which even conformational adjustment is not possible. SAMs of 4-mercaptobiphenyls are superior to those of alkanethiolates in providing stable model surfaces, as well as in the ability to engineer surface dipole moments. Coupled with the ability to engineer surface functionalities at the molecular level, SAMs and mixed SAMs of rigid thiol offer unique surfaces for nucleation and growth of inorganic and organic crystals.
Silane SAMs have been used to promote heterogeneous nucleation and growth of iron hydroxide crystals and to study the effect of surface chemistry on calcite nucleation, attachment, and growth. For example, CaCO3 has been crystallized on surfaces of alkanethiolate SAMs on gold and SAMs of functionalized alkanethiols can control the oriented growth of calcite. Also, The heterogeneous nucleation and growth of malonic acid (HOOCCH2COOH) has occurred on surfaces of alkanethiolate SAMs on gold that terminated with carboxylic acid and with methyl groups. However, while SAMs have been used to grow crystals, specifically patterned SAMs have not been used to limit the dimensions and sizes of crystals, or to grow distinct crystal of selected dimensions and sizes.
U.S. Pat. No. 6,645,293 to Allan S. Myerson discloses methods for the crystallization of nano-size crystals of molecular organic compounds while operating at a low supersaturation. The methods are based on controlling the domain size available during the crystallization process. In one method, microcontacted printed self-assembled monolayers (SAMs) with local domain area sizes ranging from 25 μm2 to 2500 μm2 and fabricated SAMs generated from electron beam lithography, are employed to control the size, orientation, phase, and morphology of the crystal. In another method, a continuous micro-crystallizer having a vessel diameter of 25 microns or less is used to ensure that that the maximum size of the crystals in two dimensions is constrained by the vessel itself. Both methods allow control of supersaturation and growth conditions, as well as manageability over crystallinity and polymorphism, and each method's domain size has the potential for further reduction.
Although there are methods for initiating crystallization (including nucleation rates) and growing crystals (including affecting the polymorphic selectivity, patterning of crystal, crystal morphology, and orientation of the crystals), there is a need for screening and characterizing the crystals produced, for further research on the crystals and for producing crystals of a desired morphology, polymorphic form and stability, among other characteristics. Therefore, it can be seen that there is a need for a method for producing crystals of both a desired structure and a desired size under modest supersaturation conditions in conjunction with a method for screening the crystals for characteristics such as morphology, polymorphic form and stability.